The TPTE gene family: cellular expression, subcellular localization and alternative splicing.

The human TPTE (Transmembrane Phosphatase with TEnsin homology) gene family encodes a PTEN-related tyrosine phosphatase with four potential transmembrane domains. Chromosomal mapping revealed multiple copies of the TPTE gene on chromosomes 13, 15, 21, 22 and Y. Human chromosomes 13 and 21 copies encode two functional proteins, TPIP (TPTE and PTEN homologous Inositol lipid Phosphatase) and TPTE, respectively, whereas only one copy of the gene exists in the mouse genome. In the present study, we show that TPTE and TPIP proteins are expressed in secondary spermatocytes and/or prespermatids. In addition, we report the existence of several novel alternatively spliced isoforms of these two proteins with variable number of transmembrane domains. The latter has no influence on the subcellular localization of these different peptides as shown by co-immunofluorescence experiments. Finally, we identify another expressed TPTE copy, mapping to human chromosome 22, whose transcription appears to be under the control of the LTR of human endogenous retrovirus RTVL-H3.

Clinicopathologic and molecular analysis of a choroidal pigmented schwannoma in the context of a PTEN hamartoma tumor syndrome.

PURPOSE: To report the first case of choroidal schwannoma in a patient affected by PTEN hamartoma tumor syndrome (PHTS) and investigate the molecular involvement of the phosphatase and tensin homolog (PTEN) and neurofibromin 2 (NF2) genes in this rare intraocular tumor. DESIGN: Observational case report. PARTICIPANT: A 10-year-old girl diagnosed with PHTS. METHODS: The enucleated specimen underwent histologic, immunohistochemical, and transmission electronic microscopy. The expression of PTEN and NF2 and their protein products were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry. Somatic mutations of PTEN and NF2, as well as allelic loss, were investigated by direct sequencing of DNA extracted from the tumor. PTEN epigenetic silencing was investigated by pyrosequencing. MAIN OUTCOME MEASURES: Histopathologic and molecular characterization of a choroidal pigmented schwannoma. RESULTS: Histopathologic, immunohistochemical, and electron microscopic analysis demonstrated features consistent with a pigmented cellular schwannoma of the choroid. We found no loss of heterozygosity at the genomic level for the PTEN germline mutation and no promoter hypermethylation or other somatic intragenic mutations. However, we observed an approximate 40% reduction of PTEN expression at both the mRNA and the protein level, indicating that the tumor was nonetheless functionally deficient for PTEN. Although DNA sequencing of NF2 failed to identify any pathologic variants, its expression was abolished within the tumor. CONCLUSIONS: We report the first description of a pigmented choroidal schwannoma in the context of a PHTS. This rare tumor showed a unique combination of reduction of PTEN and absence of NF2 expression.

Global radiolarian zonation for the Pliensbachian, Toarcian and Aalenian

Jurassic radiolarians from 220 samples in Queen Charlotte Islands, B.C., Williston Lake, B.C., east-central Oregon, Baja California Sur, southern Spain, Austria, Slovenia, Turkey, Oman, Japan and Argentina were studied in order to construct global zonation for the Pliensbachian, Toarcian and Aalenian stages. Well-preserved faunas from continuous stratigraphic sections in Queen Charlotte Islands provide the most detailed record for this time interval, and all collections are tied to North American ammonite zones or assemblages. Collections from nearly all other areas lack independent dating except for early Toarcian carbon-isotope dating in Slovenia and late Aalenian ammonites in Spain. A database of 197 widely distributed updated taxonomic species was used to construct a Unitary Association (UA) zonation for the interval. A global sequence of 41 UAs was obtained for the top of the Sinemurian to the base of the Bajocian. The first and the last UAs represent the Late Sinemurian and the Early Bajocian respectively. The remaining 39 UAs were merged into nine zones (four Early Pliensbachian, one Late Pliensbachian, one Early Toarcian, one Middle-Late Toarcian, and two Aalenian) according to prominent radiolarian faunal breaks and ammonite data. The new zones are the Canutus tip pen - Katroma clara Zone (latest Sinemurian/earliest Pliensbachian); Zartus mostleri - Pseudoristola megaglobosa, Hsuum mulleri - Trillus elkhornensis and Gigi fustis - Lantus sixi zones (Early Pliensbachian); Eucyrtidiellum nagaiae - Praeparvicingula tlellensis Zone (Late Pliensbachian); Napora relica - Eucyrtidiellum disparile Zone (Early Toarcian); Elodium pessagnoi - Hexasaturnalis hexagonus Zone (Middle and Late Toarcian); Higumastra transversa - Napora nipponica Zone (early Aalenian); and Mirifusus proavus - Transhsuum hisuikyoense Zone (late Aalenian). These zones can be correlated worldwide and link previously established UA zonations for the Hettangian-Sinemurian and the Middle to Upper Jurassic. The new zonation allows high-resolution dating in the studied interval and provides a solid basis for analyzing faunal turnovers and the paleobiogeography of Jurassic radiolarians. (C) 2010 Elsevier B.V. All rights reserved.

Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma.

BACKGROUND: Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. METHODS: We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. RESULTS: Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. CONCLUSION: TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.